Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers.

Autor: Nasser A; Supernus Pharmaceuticals, Inc., Rockville, Maryland., Randall Owen J; Navitor Pharmaceuticals, Inc., Boston, Massachusetts., Gomeni R; Pharmacometrica, Lieu-dit Longcol, La Fouillade, France., Kosheleff AR; Supernus Pharmaceuticals, Inc., Rockville, Maryland., Portelli J; Supernus Pharmaceuticals, Inc., Rockville, Maryland., Adeojo LW; Supernus Pharmaceuticals, Inc., Rockville, Maryland., Hughes TE; Navitor Pharmaceuticals, Inc., Boston, Massachusetts. Electronic address: thughes@navitorpharma.com.
Jazyk: angličtina
Zdroj: Clinical therapeutics [Clin Ther] 2024 Mar; Vol. 46 (3), pp. 217-227. Date of Electronic Publication: 2024 Mar 13.
DOI: 10.1016/j.clinthera.2023.12.015
Abstrakt: Purpose: NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine).
Methods: Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations.
Findings: Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication.
Implications: The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.
Competing Interests: Declaration of competing interest This trial was jointly sponsored by Supernus Pharmaceuticals, Inc. and Navitor Pharmaceuticals, Inc. The sponsor (Supernus Pharmaceuticals) worked with Navitor Pharmaceuticals to develop the study design. Supernus Pharmaceuticals funded the pharmacological analysis; they also conducted a courtesy legal review; however, the final content was at the discretion of the authors. Supernus Pharmaceuticals is responsible for any publication fees. Pharmacological analysis was conducted by Roberto Gomeni and funded by Supernus Pharmaceuticals, Inc. Azmi Nasser, Alisa R. Kosheleff, Jeanelle Portelli, and Lilian W. Adeojo were employees of Supernus Pharmaceuticals at the time of this work. J. Randall Owen and Thomas E. Hughes are employees of Navitor Pharmaceuticals, Inc. Roberto Gomeni has been a paid consultant to Biomedical Science Institutes, F. Hoffmann-La Roche, Indivior, Ironshore Pharmaceuticals, Janssen Research & Development, Laboratorios Liconsa, Nanomi BV, Massachusetts General Hospital, Recordati Rare Diseases, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Teva, Tris Pharma, and UCB.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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